This invention relates to 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxides and to 3,3-disubstituted-2,3-dihydronaphtho[1,8-de]-1,2-thiazine-1,1-dioxides useful in the preparation of sulfam(na)phthaleins derived from certain perhalomethylcarbinol-substituted phenols and 1-naphthols and to the preparation of said 3,3-disubstituted compounds.
2. Description of the Prior Art
Various procedures have been reported for synthesizing 3-substituted-benz[d]isothiazole-1,1-dioxides and 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxides from saccharin (3-oxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide) and from saccharin pseudo-chloride (3-chlorobenz[d]isothiazole-1,1-dioxide). As reported by A. Mustafa et al, J. Chem. Soc., 1952, p. 1339, the treatment of saccharin pseudo-chloride with excess phenylmagnesium bromide gave the corresponding 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide in almost quantitative yield. Methyl-, ethyl-, n-propyl- and n-butylmagnesium halides were reported by these authors to react analogously. R. A. Abramovitch et al, J. Chem. Soc., Perkin Trans I, 1974(22), p. 2589, reviewed and reinvestigated the reactions of saccharins with alkyl and aryl Grignard reagents and found that either the 3-alkyl (or 3-aryl) -benz[d]-isothiazole-1,1-dioxide and/or the open-chain tertiary alcohol, o-CH.sub.2 OH benzenesulfonamide wherein R is alkyl (or aryl) were obtained with one exception. When saccharin was treated with an excess of phenylmagensium bromide in boiling tetrahydrofuran, 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide was obtained as the minor product together with the open-chain tertiary alcohol.
R. A. Abramovitch et al also investigated the reaction of saccharin and saccharin pseudo-chloride with organolithium compounds and found that the reaction of saccharin with alkyl- and aryllithium compounds, such as, n-butyllithium and p-methoxyphenyllithium in tetrahydrofuran at -78.degree. C. gave the corresponding 3-substituted-benz[d]-isothiazole-1,1-dioxide, exclusively. In addition to this general method for synthesizing 3-alkyl (or 3-aryl)-benz[d]-isothiazole-1,1-dioxides, the authors reported that the reaction of the pseudo-chloride with organolithium compounds, such as, n-butyllithium in tetrahydrofuran at -78.degree. C. gave the corresponding 3,3-disubstituted-2,3-dihydrobenz[d]-isothiazole-1,1-dioxide as the major product.
Besides the reactions with Grignard and organolithium reagents, Friedel-Crafts reactions with the saccharins also have been disclosed. Dutt, J. Chem. Soc., 121, p. 2389 (1922) reported that condensation of saccharin with aromatic amines and phenols in the presence of concentrated sulfuric acid and also in the presence of fused zinc chloride. The resulting condensation products with saccharin were named "sulfamphthaleins" by analogy to "phthaleins" and "sulfonephthaleins". Though the structure of 3,3-di(4'-hydroxyphenyl)-2,3-dihydrobenz[d]isothiazole-1,1-dioxide (named "phenolsulfamphthalein") was assigned to the condensation product obtained with saccharin and phenol, it has been determined that the compound corresponding to the proposed structure has properties different from those reported, for example, colorless rather than pink in alkali and also, that the compound corresponding to the structure given could not be synthesized by repeating the procedures reported by Dutt.
Copending U. S. patent application Ser. No. 836,010 of Stanley M. Bloom, Alan L. Borror and James W. Foley filed Sept. 23, 1977 is directed to a method of synthesizing phenol and 1-naphthol sulfamphthaleins and sulfamnaphthaleins possessing a carbonyl group in the 2-position of the sulfam(na)phthalein ring. As disclosed and claimed therein, the method of preparing these compounds comprises reacting a 3-(4'-OP-1'-phenyl/4'-OP-1'-naphthyl)-3-(phenyl/naphthyl)-2,3-dihydrobenz[ d]isothiazole-1,1-dioxide (or 2,3-dihydronaphtho[1,8-de]-1,2-thiazine-1,1-dioxide) wherein P is a protecting group with a carboxylic acid halide to yield the corresponding 2-carbonyl derivative followed by removing the protecting group with weak acid to yield the product.
The 3-(4'-OP-1'-phenyl/4'-OP-1'-naphthyl)-3-(phenyl/naphthyl)-2,3-dihydrobenz[ d]isothiazole-1,1-dioxides employed as starting materials in the above method may be synthesized by reacting a 3-(4'-OP-1'-phenyl/4'-OP-1'-naphthyl)benz[d]-isothiazole-1,1-dioxide and a phenyllithium or a naphthyllithium reagent as disclosed and claimed in copending U. S. patent application Ser. No. 836,008 of Alan L. Borror, Louis Cincotta, James W. Foley and Marcis M. Kampe filed Sept. 23, 1977. As discussed therein, the 3-(4'-OP-1'-phenyl/4'-OP-1'-naphthyl)benz[d]isothiazole-1,1-dioxides are prepared by blocking the functional hydroxy group and any substituent group(s), as may be appropriate, of the selected 4-halophenol or 4-halo-1-naphthol and converting the blocked phenol or 1-naphthol to the corresponding Grignard or lithium reagent which is then reacted with a saccharin reagent. The phenyl- or naphthyllithium reagent reacted with the 3-(4'-OP-1'-phenyl/4'-OP-1'-naphthyl)benz[d]isothiazole-1,1-dioxide may be substituted or unsubstituted and may be prepared from the corresponding halo-substituted compound by reacting with lithium metal or n-butyllithium to yield the lithium reagent. If substituents, such as, hydroxy, are present, they are blocked with the appropriate protecting group to render them compatible with organometallic reagents prior to conversion to the lithium compound. The protecting groups selected should be removable under mildly acidic conditions so that the blocked substituents can be regenerated simultaneously with the regeneration of the functional --OH group of the 4'-OP-1'-phenyl or 4'-OP-1'-naphthyl moiety. Starting materials for use in the method of aforementioned application Ser. No. 836,010 also may be prepared according to the method of copending U.S. patent application Ser. No. 836,025 of Alan L. Borror, James W. Foley, Marcis M. Kampe and John W. Lee, Jr. filed Sept. 23, 1977, which comprises reacting a 3-(phenyl/naphthyl)-benz[d]isothiazole-1,1-dioxide and a 4'-OP-phenyl/ 4'-OP-naphthyllithium compound to give the corresponding 3-(phenyl/naphthyl)-3-(4'-OP-1'-phenyl/4'-OP-1'-naphthyl)-2,3-dihydrobenz[ d]isothiazole-1,1-dioxide wherein P represents a protecting group compatible with organometallic reagents which is capable of being removed in weak acid to regenerate the free --OH.
The present invention is concerned with a method of reacting a certain class of unprotected phenols and 1-naphthols with a 3-substituted-benz[d]isothiazole-1,1-dioxide or a 3-substituted-naphtho[1,8-de]-1,2-thiazine-1,1-dioxide and to the corresponding 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxide (or 2,3-dihydronaphtho[1,8-de]-1,2-thiazine-1,1-dioxide)produced.